Stereoselective Synthesis of Fluoroalkenoates and Fluorinated Isoxazolidinones: N‐Substituents Governing the Dual Reactivity of Nitrones

New derivatives of α-phenyl-N-tert-butyl nitrone (PBN) bearing a hydroxyl, an acetate, or an acetamide substituent on the N-tert-butyl moiety and para-substituted phenyl or naphthlyl moieties were synthesized. Their ability to trap hydroxymethyl radical was evaluated by electron paramagnetic resonance spectroscopy. The presence of two electron-withdrawing substituents on both sides of the nitronyl function improves the spin-trapping properties, with 4-HOOC–PBN–CH2OAc and 4-HOOC–PBN–CH2NHAc being ∼4× more reactive than PBN. The electrochemical properties of the derivatives were further investigated by cyclic voltammetry and showed that the redox potentials of the nitrones are largely influenced by the nature of the substituents both on the aromatic ring and on the N-tert-butyl function. The acetamide derivatives PBN–CH2NHAc, 4-AcNHCH2–PBN–CH2NHAc, and 4-MeO–PBN–CH2NHAc were the easiest to oxidize. A computational approach was used to rationalize the effect of functionalization on the free energies of nitrone reactivity with hydroxymethyl radical as well as on the electron affinity and ionization potential. Finally, the neuroprotection of the derivatives was evaluated in an in vitro model of cellular injury on cortical neurons. Five derivatives showed good protection at very low concentrations (0.1–10 μM), with PBN–CH2NHAc and 4-HOOC–PBN being the two most promising agents.

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“…HR-MS (ESI/Q-TOF) m / z : [M + H] + calcd for C 15 H 18 NO, 228.1388; found, 228.1396. The spectral data was in agreement with the literature …”

Section: Methodssupporting

confidence: 90%

Substituted α-Phenyl and α-Naphthlyl-N-tert-butyl Nitrones: Synthesis, Spin-Trapping, and Neuroprotection Evaluation

et al. 2020

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“…In our previous report19 we considered IN (Scheme ), formed from complex SC through TS‐B1 , as the final product of the reaction. However, the reaction can continue through two alternative diastereomeric channels to form cyclic cis and trans products PR which evolve to the isoxazolidin‐2‐one 4 observed experimentally (Scheme ) 6a,20c,31…”

Section: Resultsmentioning

confidence: 97%

Mechanism Switch in Mannich‐Type Reactions: ELF and NCI Topological Analyses of the Reaction between Nitrones and Lithium Enolates

et al. 2015

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The mechanism of the addition of lithium enolates derived from esters, ketones and aldehydes to nitrones (Mannich‐type reaction) has been studied using DFT methods. While the reactions with α‐methoxy and α‐methyl enolates takes place through a stepwise mechanism, consisting of an initial nucleophilic attack of the enolate to the nitrone carbon followed by a second nucleophilic attack of the nitrone oxygen to the formed carbonyl group, the reaction with α‐unsusbtituted enolates takes place through a one‐step mechanism. The IRC analysis shows the presence of a hidden intermediate in agreement with one kinetic step two stages process. The topological analysis of the electronic localization function (ELF) confirms that only when the first C–C bond is formed, does the C–O bond formation begin. The NCI analyses, are also in agreement with the formation of intermediates for α‐methoxy and α‐methyl enolates and a highly asynchronous one‐step process in the case of α‐unsusbtituted enolates.

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“…The shi of the uorine in this position is consistent with similar structures reported. 32 The monouorinated product could also be assigned to the coupling constant of 47.7 Hz in the proton spectra, see Fig. 5.…”

Section: Electrophilic Uorinationsmentioning

confidence: 95%

A self optimizing synthetic organic reactor system using real-time in-line NMR spectroscopy

et al. 2015

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Stereoselective Synthesis of Fluoroalkenoates and Fluorinated Isoxazolidinones: N‐Substituents Governing the Dual Reactivity of Nitrones

Cited by 19 publications

References 98 publications

Substituted α-Phenyl and α-Naphthlyl-N-tert-butyl Nitrones: Synthesis, Spin-Trapping, and Neuroprotection Evaluation

Substituted α-Phenyl and α-Naphthlyl-N-tert-butyl Nitrones: Synthesis, Spin-Trapping, and Neuroprotection Evaluation

Mechanism Switch in Mannich‐Type Reactions: ELF and NCI Topological Analyses of the Reaction between Nitrones and Lithium Enolates

A self optimizing synthetic organic reactor system using real-time in-line NMR spectroscopy

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